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Human polyomavirus 6 differentially infects healthy and tumor tissue in the colon: A case report
No full textINTRODUCTION: Human polyomavirus 6 (HPyV6) is part of the human skin virome. Like other HPyVs, it encodes proteins with oncogenic properties. MATERIALS AND METHODS: A 73-year-old Italian female patient with stage II right-sided colon adenocarcinoma underwent hemicolectomy; she died one month later because of bacterial sepsis. Colon tumor (T), adjacent healthy (AH) tissue, and serum samples were collected. Total nucleic acids were subjected to next-generation sequencing, followed by metagenomics analysis. HPyV detection was confirmed by real-time PCR and Rolling Circle Amplification (RCA); HPyV6 transcripts and proteins were identified by means of PCR and Western blot/mass spectrometry, respectively. RESULTS: Viral metagenomics analysis revealed the presence of several viral genomes, mainly belonging to unclassified viruses and phages, in both AH and T tissues. HPyV6 DNA was detected in the T tissue, representing 7 % of the viral sequences, but not in the AH tissue. Subsequent molecular analysis confirmed the presence of the HPyV6 genomes (3.3x106copies/ug) as episomes, infecting 19.8 % of the tumor cells; LT-Ag and VP1 transcripts were expressed in the T tissue, and the LT-Ag protein was expressed twice as highly in the T tissue as in the AH tissue. CONCLUSIONS: This is the first report of the differential presence and expression of the HPyV6 genome in colon tumors but not in the AH tissue. These results are indicative of ongoing active replication of the virus, which might play a triggering role in malignant transformation
Neurotrophic modulation restores motor and developmental defects in zebrafish models of ints11 deficiency
No full textMutations in INTS11, the catalytic subunit of the Integrator complex essential for RNA processing and transcriptional termination, have been linked to neurodevelopmental disorders (NDDs), yet the underlying mechanisms remain poorly understood. To address this gap, we developed and characterized a novel ints11 loss-of-function zebrafish model using CRISPR/Cas9 and morpholino-based approaches, which recapitulates key phenotypic traits observed in human patients, including motor and behavioural deficits. ints11 deficiency led to marked impairments in locomotor activity and circadian rhythmicity, consistent with the neurological manifestations reported in INTS11-mutated patients. These behavioural abnormalities were paralleled by significant dysregulation of neurodevelopmental gene expression, including decreased expression of islet1, map2, gfap, and mag, and upregulation of the progenitor marker nestin, indicating defective neuronal differentiation and glial maturation. Interestingly, the observed phenotypes are rescued not only by mRNA-mediated re-expression of ints11, but also through pharmacological administration with brain-derived neurotrophic factor (BDNF) and the GM1 ganglioside-derived oligosaccharide (OligoGM1). These findings highlight neurotrophic signaling as a potential compensatory axis counteracting RNA-processing defects. In conclusion, our work establishes the first in vivo zebrafish model of INTS11-associated neurodevelopmental dysfunction, uncovering conserved molecular mechanisms that link Integrator complex activity, neurotrophic support, and neuronal maturation and providing a valuable platform for dissecting disease mechanisms and evaluating therapeutic strategies targeting RNA processing pathways and neurotrophic support in NDDs
Mechanisms associated with progression from lobar inflammation to bilateral lung injury: an experimental study
No full textBackground
Localized lung insult, such as pneumonia, can increase respiratory drive and effort. The interplay between the initial injury, the inflammatory reaction and increased drive and effort could damage other areas and progress to bilateral lung injury.
Methods
Localized pulmonary inflammation was induced through instillation of 0.5 mg/kg lipopolysaccharide (LPS) in the left lower lobe of 18 pigs, while 5 animals served as sham controls. After 24 hours of spontaneous breathing, the severity of right lung injury was assessed by the validated histological score and correlated with potential physiological and biological determinants.
Results
Animals challenged with lobar inflammation developed bilateral lung injury, associated with increased respiratory drive and effort.
Histological score of the right lung was characterized by wide inter-individual variability (median 11 [8-14], range 3-25). Right lung injury score was correlated with respiratory drive and effort; with respiratory rate and minute ventilation, but not with tidal volume; with peak inspiratory and driving transpulmonary pressures, and with EIT-derived lung strain; with lower sub-atmospheric alveolar pressure and with more negative end-expiratory transpulmonary pressure.
Right lung injury score was also correlated with inflammatory plasma cytokines: higher SDF-1α and lower IL-1Ra, IL-5 and GM-CSF.
Conclusions
An experimental model of localized lung inflammation allowed us to investigate the role of specific pathophysiological mechanisms for the development of injury in previously healthy lung regions
Alkynes Hydration in Three‐Component Double‐Acidic Deep Eutectic Solvents
No full textIn this work, a sustainable method for the hydration of both terminal and internal alkynes is presented, affording the corresponding ketones with complete Markovnikov regioselectivity. The key advantage of this approach lies in the use of recently developed three-component, double-acidic deep eutectic solvents (DESs), designed by our research team, which act as triple-active media—simultaneously serving as solvents, reagents, and catalysts. The reaction setup is straightforward and can be carried out under conventional or dielectric heating, typically providing the desired products in good to excellent yields. For terminal alkynes, microwave heating further enhances the sustainability of the process by a significant reduction of reaction times. The reusability of the reaction medium is demonstrated through recycling experiments, while the calculation of two green metrics (sE-factor and EcoScale) highlights the environmental benefits of this strategy
Validation of the QAMAI tool in Italian for the evaluation AI-generated health information in head and neck surgery
No full textBACKGROUND: This study aimed to validate the Italian version of the Quality Assessment of Medical Artificial Intelligence (IT-QAMAI) tool, designed to evaluate the reliability of AI-generated health information in the context of head and neck surgery.
METHODS: The IT-QAMAI tool was adapted from the original English version and involved a rigorous translation and back-translation process. The validation involved 18 researchers from 13 centers across Europe, assessing 24 AI-generated responses categorized into clinical scenarios, theoretical questions, and patient inquiries. The tool’s reliability was measured using Cronbach’s alpha for internal consistency, the Intraclass Correlation Coefficient (ICC) for inter-rater reliability, and Pearson’s correlation for test-retest reliability.
RESULTS: The IT-QAMAI demonstrated high internal consistency (Cronbach’s alpha = 0.850) and good inter-rater reliability (ICC=0.750). Test-retest reliability was strong (rs=0.887). Significant differences were found in the quality of AI-generated responses across different question types.
CONCLUSIONS: The IT-QAMAI tool is a reliable and valid instrument for assessing the quality of AI-generated health information in Italian, with significant implications for its use in clinical practice and research in head and neck surgery
Integrated Optimization of Building and Curing in Tires Production
No full textWe address the problem of optimally planning the two main phases in tires production, namely building and curing. They are executed by different machines subject to specific constraints; furthermore, the buffer capacity between the two phases is limited. We present a mathematical model of the optimization problem, that turns out to be a computationally difficult MILP problem. Computational tests show that reducing the symmetries by variable aggregation allows to solve large size instances arising in a real production plant to near-optimality within a reasonable amount of computing time
DairyMix: circularity and sustainability of crop-livestock systems for dairy production in Europe and Latin America
No full textRelevant factors to guarantee quality of oligonucleotide-based products
No full textIn recent years, oligonucleotides have rapidly made their way into the market. Their development and clinical potential have made them strong candidates for addressing a variety of diseases. Oligonucleotides are synthetic chemical entities carrying unique characteristics that often require a different approach to preclinical assessment compared to small molecules. However, their unique chemical complexity presents significant challenges for both pharmaceutical development and regulatory evaluation. In this light, the work aims to review the features and current regulatory landscape of oligonucleotide and discuss the key points for assessing the quality profiles of the medicinal products containing oligonucleotide; to this end, a comprehensive review of all oligonucleotide-based medicines was conducted based on information on regulatory authorization portals such as EMA and FDA with particular focus on quality aspects. The results highlight that these complexities lie in the characterization of the active substance and drug product, especially impurity profiles, and the sterilization of these products. Current regulatory guidelines need to be routinely updated to support developers in addressing these complexities and it is crucial to understand the critical quality attributes of oligonucleotides and their control strategies for researchers in the initial stages of R&D
Correlations between the metabolic costs of level and graded running: A secondary analysis of the literature metabolic cost of graded
No full textBackground: The metabolic cost of running (Cr) is one of the three main determinants of performance in distance running, along with maximum oxygen consumption and lactate threshold. However, level Cr is only weakly correlated with performance in trail running, which almost always involves uphill and downhill sections.
Objective: Through a secondary analysis of published data, the primary aim of this study was to characterize the correlations between individuals' level and graded (downhill and uphill) Cr. We took advantage of this database to also re-evaluate the pattern and critical points (i.e., optimum slope) of the relationship between Cr and slope.
Methods: We analyzed 23 studies evaluating level and graded Cr, published before August 2024. Both Cr and Pearson correlation coefficients between level and graded Cr were plotted as functions of slope.
Results: Using third-order polynomial functions, a correlation between level and graded Cr was a continuous function of slope in which correlation coefficients declined with progressively steep uphill or downhill slopes. Downhill Cr was minimized at - 18.8%, and a linear relationship was observed for uphill Cr with slope across the range of slopes analyzed (up to + 26.8%).
Conclusions: The present secondary analysis extends our knowledge on the influence of slope on Cr, showing that graded Cr is weakly correlated with level Cr when slope is steeper than ± 10%. Consequently, testing and training protocols for trail runners should incorporate steeper slopes (i.e., ± 15%) to provide more relevant assessments and preparation for mountainous trail races (including steep slopes)